Compounds and methods for amino-alkylenediol synthesis

ABSTRACT

A method of making an amino-alkylenediol and intermediate compounds useful in the method is disclosed. The method includes preparing a first intermediate compound comprising an aminoalkylene diol wherein a protecting group is linked to the amino functionality, and optionally, preparing a second intermediate compound comprising a salt of the first intermediate compound. 
     The first intermediate compound has the structure 
     
       
         
         
             
             
         
       
     
     wherein R is a divalent alkylene radical having from 2 to 20 carbon atoms, X and Y are independently a divalent linking moiety or a single bond, and Z is a protecting group. 
     The second intermediate compound has the structure 
     
       
         
         
             
             
         
       
     
     wherein R is a divalent alkylene radical having from 2 to 20 carbon atoms, X and Y are independently a divalent linking moiety or a single bond, TsO −  is toluene sulfonate, and Z is a protecting group.

PRIORITY CLAIM

The present non-provisional patent Application claims benefit from U.S.Provisional Patent Application having Ser. No. 60/876,828, filed on Dec.22, 2006, by Wong, and titled COMPOUNDS AND METHODS FORAMINO-ALKYLENEDIOL SYNTHESIS, wherein the entirety of said provisionalpatent application is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds and methods useful in thesynthesis of amino-alkylenediols. More particularly, the presentinvention relates to intermediate compounds and the preparation of theseintermediate compounds that comprise a protecting group that facilitatesthe isolation of the amino-alkylenediol in an aqueous environment.

BACKGROUND

Amino-alkylenediols, such as 3-amino-1,5-pentanediol are introduced as akey fragment in the synthesis of pyridopyrimidines and derivativesthereof such as hydroxyalkyl substituted pyrido-7-pyrimidin-7-ones. Thepyridopyrimidines and their derivatives are useful in treating variousdisorders in a patient and are currently being evaluated as P38(4) MAPKinase Inhibitors in treatment for rheumatoid arthritis. The preparationof these materials is known. See for example United States PatentApplication Publication 2005/0107408 A1 and WO 2002/2064594 A2.

There are various known methods of synthesizing theseamino-alkylenediols. However, these methods often involve synthesis inan aqueous system using reactions that require aqueous work upprocedures. The hydrophilic nature of the aminodiol moiety makes itdifficult and inefficient to manufacture these compounds in high yield.Significant loss in yield often occurs in the final extraction of theseproducts from the aqueous environment. Accordingly, there exists a needfor a new method to make these compounds economically and in high yield.

SUMMARY

The present invention achieves this result. It provides a method andintermediate compounds that facilitates the manufacture ofamino-alkylenediols economically and in high yield by allowing isolationof the intermediate compounds in an aqueous environment, and the finalproduct in a non-aqueous environment.

The amino-alkylenediols have the structure

wherein R is an alkylene group having from 2 to 20 carbon atoms. In oneembodiment, R in Compound I has the formula —CH₂(CH₂CH(NH₂)CH₂)_(n)CH₂₋—wherein n is an integer of from 1 to 6.

In one embodiment, the method of the invention comprises theintroduction of an organic “handle” or “handles” such that theintermediate compounds may be extracted from an aqueous environmentefficiently. The handle or handles are referred to hereinafter as aprotecting group. The protecting group is linked to the aminofunctionality of the intermediate compounds (Compounds II and III).Compound III comprises a salt of Compound II. The salt may besubsequently reduced to a purified form of the first intermediatecompound.

In another aspect of the invention, the first intermediate compound(Compound II) is converted to the amino-alkylenediol (Compound I). Aspecific embodiment of this method comprises reducing adialklyl(amino)alkyl enamine (e.g., benzylenaminediester) to adialkyl(amino)alkyl diester (e.g., benzylaminodiester), subsequentlyreducing the diester to the first intermediate compound, which may beextracted from an aqueous medium, and then converting the firstintermediate directly to the amino-alkylenediol (Compound I) by, forexample, removal of the benzyl group(s) via hydrogenation orhydroformylation in a non-aqueous environment.

In yet another aspect of the invention, a purified form of the firstintermediate compound is prepared from the second intermediate afterwhich the purified first intermediate compound may be converted to theamino-alkylenediol (Compound I) by, for example, the method(s) set forthin the previous paragraph.

The present invention also provides novel intermediate compounds. Oneintermediate compound of the invention comprises a laminodiol having abenzyl group linked at the nitrogen. Another intermediate compound ofthe invention comprises a salt of the benzylamino diol.

The first intermediate compound may be represented by the formula:

wherein R is as defined above, X and Y are independently a divalentlinking moiety or a single bond, and Z is the protecting group.

The second intermediate compound may be represented by the formula:

wherein R, X, Y and Z are as described above, and TsO⁻ is p-toluenesulfonate (i.e., CH₃C₆H₄SO₂—).

DETAILED DESCRIPTION

As used herein, the following terms have the following meanings, unlessotherwise indicated:

“Alkyl” means a linear or branched monovalent, saturated hydrocarbonradical having from 1 to 20 carbon atoms that may optionally contain oneor more heteroatoms therein.

“Alkylene” means a divalent linear or branched, saturated hydrocarbonradical having from 2 to 20 carbon atoms that may optionally contain oneor more heteroatoms.

“Protecting group” means an atom or grouping of atoms that when linkedto the amino group reduces the reactivity of the amino group byprotecting it from unwanted side reactions. Examples of protectinggroups can be found in T. W. Green and P. G. Futs, Protective Groups inOrganic Chemistry, (Wiley 2^(nd) ed., 1991) and Harrison and Harrison etal, Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley andSons, 1971-1996). Representative examples of useful protecting groupsinclude formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl,tert-butoxycarbonyl, trimethyl silyl, 2-trimethylsilyl-ethanesulfonyl,trityl and substituted trityl, aklyoxycarbonyl,9-fluoroenylnethyloxycarbonyl, nitro-veratryloxycarbonyl, andcombinations thereof.

“Divalent linking moiety” means a moiety that links two atoms or groupstogether. Examples of divalent linking moieties useful in the inventioninclude an alkylene radical, a cycloalkylene radical, an arylalkyleneradical, and combinations thereof.

Turning now to the various embodiments of the invention identifiedabove, the method comprises the preparation of a first intermediatecompound (Compound II). This may be accomplished by a variety of methodsknown in the art. One method for preparing the first intermediatecompound is shown in Scheme 1 below.

Compound IIB can be prepared by reducing Compound IIA using any of anumber of reducing agents. This reduction can be readily carried out ina solvent that is inert under the conditions of the reaction.

Examples of useful reducing agents and acids include sodium boronhydride in acetic acid (NaBH₄/HOAc), sodium boron hydride in methanol(NaBH₄/MeOH), sodium boron hydride in phosphoric acid (NaBH₄/H₃PO₄) andtert-butyl amino borane in sulfuric acid (t-BuNH₂.BH₃ in H₂SO₄, alsoreferred to herein as TBAB), and NaH₂Al(OCH₂CH2)C₂H₅ (also referred toherein as Vitride). Suitable solvents for use in the reaction includetoluene, tetrahydrofuran (THF), etc. The reduction can be carried out ata temperature of from about −20° C. to about 120° C. Typically thereduction is carried out at a temperature in the range of from about−20° C. to 40° C.

Reduction of Compound IIB provides the Compound II. This reduction maybe carried out with NaBH₄ in an appropriate but optional solvent (e.g.,MeOH) in refluxing THF. Less than 3 equivalents of the reducing agent(e.g., NaBH₄) are needed to allow the reaction to go to completion. Thereduction can be carried out at a temperature of from about −20° C. toabout 120° C. Typically the reduction is carried out at a temperature offrom about −10° C. to 30° C.

The method of the invention may comprise the optional step of preparingsecond intermediate compound (Compound III). This step is useful inremoving impurities formed during preparation of the first intermediate(Compound II). An illustrative method for preparing the secondintermediate compound is shown in Scheme 2 below.

This process comprises forming a tosylate salt of Compound II,crystallizing that salt and isolating that salt by reacting Compound IIwith an appropriate acid (e.g., para-toluene sulfonic acid),crystallization of the salt in solvent (e.g., THF/CH₂Cl₂) and isolationof the salt.

Conversion of the tosylate salt (Compound III) to a purified form of thefirst intermediate compound has been found to improve the yield of thedesired amino-alkylenediol (Compound I). An illustrative method ofpreparing a purified version of the first intermediate compound is shownin Scheme 3.

In this method, Compound II is formed from Compound III by adjusting thepH of a solvent solution of Compound II to a pH of from 10-14 andextracting the resulting salt with solvent (e.g., CH₂Cl₂). A recovery of96% or more can be achieved in this manner.

Compound II may be converted to the desired amino-alkylenediol by aprocess such as that shown in Scheme 4.

The transformation of Compound II to Compound I may be accomplished byany of a number of processes. For example, Compound II may be dissolvedin a solvent or blend of solvents and then charged to a pressure reactoralong with a suitable catalyst. The reactor can then be sealed andheated to a desired temperature. The transformation reaction is allowedto proceed, preferably with stirring for a suitable period of time. Thetransformed product (i.e., Compound I) is then recovered from thereactor.

It is to be appreciated that although the schemes illustrated aboveindicate exact structures and compositions of the various compoundsbeing prepared, the method of the present invention applies widely toany analogous compounds, given appropriate consideration to protectionof the amino functionality employed therein. That is, the aminofunctionality is shielded from unwanted side reactions during otherchemical reactions at other sites on the molecule. The protecting groupcan then be removed to provide the desired molecule (Compound I).

The preceding discussion has been directed to a multi-step process forforming Compound II. In one version, an enamine (Compound IIA) isconverted to a diester (Compound IIB) with subsequent conversion to thediol (Compound II). In another version, an intermediate step is added inwhich a purified version of Compound II is formed by converting CompoundII to a salt (Compound III) and then converting Compound III back toCompound II.

In an alternative embodiment, Compound II may be formed directly fromCompound IIA. In this embodiment, the Compound IIA may be reacted with asuitable acid to produce a slurry of the corresponding imine. Thus forexample, Compound IIA may be reacted with H₃PO₄ in dimethoxyethane (DME)to produce a slurry of the imine. The imine slurry may then be added toa slurry of NaBH₄ (e.g., 1 eq.) in DME and reacted for a desired time(e.g., 6 hours) with stirring. The reaction mixture may then be added toa second slurry of NaBH₄ (e.q., 3 eq.) in DME, and ethanol and warmed toreflux (e.g., 77° C.) until the reaction is complete. This may takeseveral hours (e.g., 12 hours or more). The reaction mixture may then becooled to room temperature (e.g., 20° C.) and added slowly to water. Asignificant amount of hydrogen may be released. When the hydrogenevolution is complete, the pH of the reaction mixture may be adjustedto, e.g., 12-13. The slurry may then be extracted several times with asuitable solvent (e.g., DME) and the resulting organic phases combinedto give Compound II. This is typically a pale yellow oil. Yields ofgreater than 65% can be achieved with this method.

The preparation of Compound II can also be accomplished in a singlereaction vessel. An illustrative example of this “one-pot” process isset forth below in Example 1. In this process, at least steps 1A through1D are carried out in a single reaction vessel.

Additional advantages, features and benefits of the present inventionwill be apparent to those of skill in the art based upon the followingillustrative examples, which are not intended to limit the presentinvention.

EXAMPLE 1

3-amino-1,5-pentane diol was prepared according to the followingprocedure.

Step 1A

Benzylenamine was reduced to benzylamino diester according to thefollowing steps:

Material MW Mmol Amount Ratio to LR Isopropanol (IPA) 16.5 ml 1.1 ml/gSulfuric acid (conc.) (H₂SO₄) 98.10 113.9 11.2 g 2 eq. tert-Butylamineborane complex (TBAB) 86.97 57.0 5.0 g 1 eq. Tetrahydrofuran (THF) 82.5ml 3.5 ml/g Benzylenamine 263.30 57.0 15.0 g LR Water 90.0 ml 6 ml/gAmmonium hydroxide (conc.) 11.9 g 0.79 g/g Dichloromethane (DCM) 2 ×52.5 ml 3.5 ml/g Brine (11 wt %) 75.0 ml 5 ml/g

A vessel is charged with 16.5 ml isopropanol cooled to 0-3° C.Concentrated sulfuric acid (11.2 g) is then slowly added, keeping theaddition temperature ≦10° C. Then 5.0 g tert-butylamine borane complex(TBAB) as a solution in 52.5 ml THF is added, keeping the additiontemperature ≦10° C. Hydrogen gas is given off through the course of theaddition. Then 15.0 g benzylenamine as a solution in 30.0 ml THF is thenadded, keeping the addition temperature ≦15° C.

After the additions are complete, the batch is warmed to 20-23° C. andstirred for at least 2 hours. A sample is taken to analyze for reactioncompletion. When the reaction is deemed complete, the batch is added to90.0 ml water. The THF is then distilled off (150 mmHg/45° C. bath), and11.9 g concentrated ammonium hydroxide is used to adjust the pH of thebatch to 9.5 (±0.5). The batch is then extracted twice with 52.5 mldichloromethane. The organic layers are combined and extracted once with75.0 ml 11 wt % brine solution. The organic phase is then stripped (300to 5 mmHg/45° C. bath) to yield the benzylaminodiester product as aclear colorless oil (97-100% yield based on benzylenamine).

Step 1B

Benzylaminodiol was prepared using the following procedure by reducingthe benzylaminodiester.

Material MW Mmol Amount Ratio to LR Benzylaminodiester 265.31 56.5 15.0g LR Tetrahydrofuran (THF) 90.0 ml 6.2 ml/g Vitride(NaH₂Al(OCH₂CH₂OMe)₂, 202.17 141.3 44.0 g 2.5 eq. 65 wt %) 20 wt %Citric acid 225.0 g 15 g/g Water 60.0 ml 4 ml/g 50 wt % NaOH 27.0 ml 1.8ml/g Dichloromethane (DCM) 2 × 101.0 ml 2 × 6.7 ml/g

A vessel is charged with 15.0 g benzylaminodiester from step 1A anddissolved in 60.0 ml THF. This is cooled to 0-3° C. Then 44.0 g vitride(65 wt % solution in toluene) is added over approximately 1 hour keepingthe addition temperature ≦110° C. The batch is then stirred at 0-10° C.for 30 minutes, and is then sampled for reaction completion. Uponreaction completion, the batch is slowly poured into 225.0 g 20 wt %citric acid (pre-cooled to 0-3° C.), keeping the addition temperature≦10° C. Hydrogen gas is given off through the course of the addition.The reaction vessel is rinsed into a quench vessel with 30.0 ml watertwice and 30.0 ml THF. The pH of the batch is then adjusted to 12.5(±0.5) with 27.0 ml 50 wt % NaOH. (All solids should dissolve at theelevated pH). The THF is then distilled from the batch (150 mm Hg/45° C.bath). The batch is cooled to 20-23° C., and is then extracted twicewith 101.0 ml DCM. The DCM phases are combined and are then concentratedto a total volume of 60 ml.

Step 1C

Benzylaminodiol tosylate was then prepared using the followingprocedure.

Material MW Mmol Amount Ratio to LR Benzylminodiol 209.29 56.4 11.8 g LRp-Toluenesulfonic acid 190.22 56.4 10.7 g 1.0 eq. hydrateTetrahydrofuran (THF) 23.6 ml 2.0 ml/g DCM 112.5 ml 9.5 ml/gBenzylaminodiol tosylate 381.49 0.013 50 mg 0.004 g/g

A vessel is charged with 10.7 g para-toluenesulfonic acid hydrate. Thehydrate is dissolved in 23.6 ml THF and 65.3 ml dichloromethane andcooled to 5-10° C. The diol solution from Step 1B is slowly added to thepTsOH solution, keeping the addition temperature ≦10° C. Whenapproximately 60% of the diol solution is added, 50 mg seed crystals ofbenzylaminodiol tosylate are added, and the batch is allowed tocrystallize for 15 minutes. Addition of the diol solution is resumed,keeping the temperature ≦10° C. The addition line is rinsed with a smallamount of DCM. After the addition is complete, the batch is stirred forat least 2 hours at 5-10° C. The batch is then filtered, and the cake isrinsed 4 times with 11.8 ml dichloromethane. The salt is dried (10mmHg/40° C./4 h) to yield the benzylaminodiol tosylate as a bright whitesolid (88-90% yield from the diester).

Step 1D

Purified benzylaminodiol was prepared according to the followingprocedure.

Material MW Mmol Amount Ratio to LR Benzylaminodiol tosylate 381.49 50.319.2 g LR DCM 132.9 ml 7.23 ml/g 1N NaOH 62.9 ml 1.25 eq. Water 55.4 ml1.1 L/mol

Benzylaminodiol tosylate from step 1C (19.2 g) is slurried in 132.9 mldichloromethane and 55.4 ml water in a suitable vessel. Then 62.9 ml 1NNaOH is added to adjust the pH of the aqueous phase to 12.5 (±0.5). Thistwo-phase mixture is stirred for 15 minutes and allowed to settle. Thebottom organic phase is separated to a separate flask. The organic phaseis heated to reflux, and the condensate is cycled through the aqueousphase to achieve a sort of continuous extraction. Samples are taken ofthe aqueous phase. The extraction is continued until analysis shows nodiol remaining in the aqueous phase. The organic phase is then stripped(300 to 5 mmHg/45° C. bath) to yield the benzylaminodiol a clearcolorless oil (92-94% yield based on the tosylate salt).

Step 1E

3-amino-1,5-pentane diol was prepared according to the followingprocedure.

Material MW Mmol Amount Ratio to LR Benzylaminodiol 209.29 239 50.0 g LR10 wt % Pearlman's Catalyst (50% wet) 3.4 g Methanol 140 mL Toluene 140mL Celite 5 g Methanol 50 mL 10 wt % Sodium Sulfite 15 mL

A pressure reactor is charged with 50% wet Pearlman's Catalyst. Thebenzylaminodiol from step 1D (50.0 g) is dissolved in methanol (140 mL)and toluene (140 mL), which is then charged to the reactor. The reactoris sealed, purged (5×35 psi H₂), pressurized with hydrogen (35 psi), andwarmed to 50° C. The batch is stirred under pressure at 50° C. for 4hours. After venting, the batch was filtered through a Celite pad (5 g)and the catalyst pad is rinsed with methanol (2×25 mL). The solvents arethen removed under reduced pressure (150 to 5 mm Hg, 45° C. bath) togive 3-amino-1,5-pentanediol product as clear colorless oil(quantitative yield).

EXAMPLE 2

3-amino-1,5-pentane diol was prepared according to the followingprocedure.

Step 2A

Benzylamino diester was prepared as described in Step 1A of Example 1.

Step 2B

Benzylaminodiester was reduced to benzylaminodiol according to thefollowing procedure.

Material MW Mmol Amount Ratio to LR Benzylaminodiester 265.3 379.6 100.7g LR THF 534 ml 5.3 ml/g Sodium borohydride (NaBH₄) 37.83 1518.2 57.4 g4 eq. Methanol 71 ml 0.71 ml/g Water 1510 ml 15 ml/g 3N HCl 297 ml 2.95ml/g DCM 3217 ml 31.95 ml/g 50% NaOH 212 ml 2.11 ml/g

In a 2 L 4-necked reactor equipped with a large nitrogen inlet, athermocouple, a reflux condenser, and a mechanical agitator, sodiumborohydride (57.4 g) is charged and slurried in THF (8 mL). In aseparate flask, the benzylaminodiester (100.7 g) is dissolved in THF(453 mL), and the resulting solution is added directly to theborohydride slurry. Methanol (72 mL) is then added with vigorousstirring. Hydrogen gas is evolved during and after the addition, so thevessel is adequately swept with nitrogen. The batch is then warmed toreflux (56° C. internal temperature, 60° C. bath) and stirred for atleast 12 hours, and tested for reaction completion.

Upon reaction completion, the batch is cooled to 0-5° C. and added towater (1510 mL; no hydrogen evolution). The batch is then stripped underreduced pressure (200 mm Hg/45° C. bath) to remove the organic solvents.The pH of the batch is then adjusted to 2-3 with 3N HCl. Acidificationof the batch causes hydrogen gas to be evolved. The vessel is wellvented, and the acid is added slowly to avoid excess frothing. Theaddition is exothermic, and the batch is kept ≦10° C. through the courseof the acidification. When the desired pH range is reached, the batch iswarmed to 20° C. and dichloromethane (297 mL) is added, the batch isstirred for 15 minutes, settled for 30 minutes, and phase separated. Theorganic phase is discarded. The product-containing aqueous (top) phaseis then cooled and made basic (pH to 11-12) by the addition of 50%sodium hydroxide. This addition is also exothermic, and cooling isrequired to keep the batch temperature ≦110° C. The batch is then warmedto 20° C., and is extracted five times with a dichloromethane (584 mLeach). The organic layers are combined and concentrated tobenzylaminodiester as a clear colorless to clear yellow oil.

Steps 2C and 2D

Purified benzylamino diol was then prepared as described in Steps 1C and1D of Example 1

Step 2E

3-amino-1,5-pentane diol was prepared according to the followingprocedure.

Th. Material MW Mmol Th. Measure Ratio to LR Benzylaminodiol 209.29238.9 50.0 g LR Pearlman's Catalyst 3.4 g 0.067 g/g Methanol 140.0 ml2.8 ml/g Toluene 140.0 ml 2.8 ml/g Celite 5.0 g 0.1 g/g Methanol 50.0 ml1 ml/g

Operations:

The Pearlman's catalyst is charged to a pressure reactor. Thebenzylaminodiol, as a solution in toluene, is then charged into thereactor. Methanol is charged to the reactor. The reactor is then sealedand purged 3× with hydrogen. The reactor is warmed to 50° C. withstirring and held at temperature for 2 hours. The reactor is then ventedand a sample is taken to measure for reaction completion. Once thereaction is complete, the batch is cooled and filtered through a Celite.The Celite is rinsed with methanol. The catalyst is deactivated with a10 wt % sodium sulfite rinse. The batch is then vacuum distilled down tothe 3-amino-1,5-pentane diol as an oil.

EXAMPLE 3

Benzyl enamine to benzyl aminodiol without intermediate isolation.

Th. Material MW Mmol Th. Measure Ratio to FL Benzylenamine 263.31 76.020.0 g LR Toluene 80.0 ml 4 ml/g Acetic acid (HOAc) 80.05 342.2 19.6 ml4.505 eq. Sodium borohydride 37.83 132.9 5.0 g 1.75 eq. Toluene 100.0 ml5 ml/g Vitride (70%) 73.0 ml 3.65 g/g HCl (30%) As specified Citric acid(10%) As specified Sodium Hydroxide (20%) As specified Water Asspecified Dichloromethane 700.0 ml 35 ml/g Toluene 400.0 ml 20 ml/g

To a stirred slurry of NaBH₄ in 100 mL of toluene cooled to −10° C. in a1000 mL 3-necked round bottom flask equipped with overhead mechanicalstirrer and a thermometer was added a solution of benzylenamine and HOAcin 80 mL of toluene in 20 min. The addition funnel was rinsed with 20 mLof toluene. The batch was allowed to stir and warm up to 15-18° C.slowly overnight. The 16 h HPLC sample showed the enamine had beenconsumed. The mixture was cooled back to −10° C. and Vitride was addedvia an addition funnel slowly in 1 hour. The batch was kept below 0° C.during the addition. After the addition, the light yellow milky mixturewas stirred at a temperature of between −5 to 0° C. HPLC after 30 min.showed 0.7% diester left. The slurry was stirred for a total of 2 hours.The batch was quenched by adding slowly to a mixed solution of 80 mL of30% aqueous HCl and 80 mL of 10% aqueous citric acid cooled at 5° C. in20 min. The temperature of the batch was not allowed to exceed 20° C.The pH at this time was about 1-2. The addition funnel was rinsed with amixture of 20 mL of 30% aqueous HCl and 20 mL of 10% aqueous citricacid. After warming up to room temperature, the layers were separated.The organic layer was extracted with 100 mL of 10% aqueous citric acid.The combined aqueous portion was then cooled to 0-5° C., and basicifiedto pH 12.5 with 245 mL of 20% aqueous NaOH. Another 50 mL of water wasused for rinsing. The cloudy mixture was then extracted with 7×100 mL ofCH₂Cl₂. During the extraction, the aqueous layer was cloudy but theorganic layer remained clear and easily separated. The combined organicportion was stripped to an oil. Then 2×200 mL of toluene was added andthe solution was stripped to a yellow oil. Toluene was then added to theresidue to give 46.2 g of a yellow benzylaminodiol solution.

EXAMPLE 4

Benzylamindiol of step 2B may be converted to the aminodiol without theuse catalytic hydrogenation. In this case, hydrogen transfer is used toremove the benzyl protecting group. Thus, 3-N-benzylpentane-1,5-diol(104.5 mg, 0.5 mmol, 1 equiv) is dissolved in a slurry of 10% Pd/C (100mg/56% wet) in anhydrous methanol (7 mL). To this is added the protonsource, ammonium formate (315 mg, 5 mmol, 10 equiv) and the mixture isrefluxed for 40 minutes. The hot solution is filtered through celite andwashed with methylene chloride (15 mL). Evaporation gives a clearcolorless oil (67 mg). Carbon 13 NMR shows the expected three carbonresonances and proton NMR also confirms the material as the desiredproduct. Gas chromatography after derivatization shows the presence ofboth the disiloxy and trisiloxy derivatives as separate peaks.

Other embodiments of this invention will be apparent to those skilled inthe art upon consideration of this specification or from the practice ofthe invention disclosed herein. Various omissions, modifications, andchanges to the principles and embodiments described herein may be madeby one skilled in the art without departing from the true scope andspirit of the invention which is indicated by the following claims.

1. A method for the synthesis of an aminoalkyl diol comprising the stepof preparing a first intermediate compound comprising an aminoalkylenediol wherein the amino functionality comprises a protecting group. 2.The method of claim 1 comprising the further steps of (i) preparing asecond intermediate compound comprising a salt of the first intermediatecompound and (ii) preparing a purified aminoalkylene diol from thesecond intermediate.
 3. The method of claim 1 wherein the step ofpreparing the first intermediate compound comprises reducing adialkyl(amino)alkyl enamine to a dialkyl(amino) alkyl diester andreducing the dialkyl(amino) alkyl diester to the first intermediatecompound.
 4. The method of claim 1 wherein the first intermediatecompound comprises the formula

wherein R is a divalent alkylene radical, X and Y are independently adivalent linking moiety or a single bond, and Z is the protecting group.5. The method of claim 4 wherein R comprises five carbon atoms, X is asingle bond, and Y is a divalent linking moiety.
 6. The method of claim1 wherein Z comprises an atom or grouping of atoms that when attached tothe amino group reduces the reactivity of the amino group.
 7. The methodof claim 6 wherein Z is selected from formyl, acetyl, trifluoroacetyl,benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, trimethyl silyl,2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl,aklyoxycarbonyl, 9-fluoroenylmethyloxycarbonyl,nitro-veratryloxycarbonyl, and combinations thereof.
 8. The method ofclaim 2 wherein the second intermediate compound comprises the formula

wherein R is a divalent alkylene radical having from 2 to 20 carbonatoms, X and Y are independently a divalent linking moiety or a singlebond, TsO⁻ is toluene sulfonate, and Z is a protecting group.
 9. Themethod of claim 1 wherein the aminoalkyl diol has the formula

wherein R is a divalent alkylene radical having from 2 to 20 carbonatoms.
 10. The method of claim 1 wherein the first intermediate compoundis derived from a benzyl enamine of the formula

wherein R¹ is an alkyl group having from 1 to 20 carbon atoms.
 11. Amethod for the synthesis of HOCH₂CH₂CH(NH)CH₂CH₂OH comprising preparinga first intermediate compound having the structure

preparing a second intermediate from the first intermediate, the secondintermediate comprising the formula

wherein TsO⁻ is p-toluene sulfonate.
 12. A compound comprising: ahydroxyl terminated divalent alkylene radical having from 2 to 20 carbonatoms; an amino group linked to one of the carbon atoms in the backbone;and a protecting group linked to the amino group.
 13. The compound ofclaim 12 wherein the amino group is linked to the third carbon atom inthe alkylene radical.
 14. The compound of claim 12 wherein theprotecting group comprises an atom or grouping of atoms that when linkedto the amino group reduces the reactivity of the amino group.
 15. Thecompound of claim 14 wherein the protecting group is selected fromformyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl,tert-butoxycarbonyl, trimethyl silyl, 2-trimethylsilyl-ethanesulfonyl,trityl and substituted trityl, aklyoxycarbonyl,9-fluoroenylmethyloxycarbonyl, nitro-veratryloxycarbonyl, andcombinations thereof.
 16. The compound of claim 12 comprising theformula the formula:


17. A compound comprising: a hydroxyl terminated divalent alkyleneradical having from 2 to 20 carbon atoms; an amino tosylate group linkedto one of the carbon atoms in the divalent alkylene radical; and aprotecting group linked to the amino tosylate group.
 18. The compound ofclaim 17 wherein the amino group is attached to the third carbon atom inthe divalent alkylene radical.
 19. The compound of claim 17 wherein theprotecting group comprises an atom or grouping of atoms that whenattached to the amino group reduces the reactivity of the amino group.20. The compound of claim 17 comprising the formula:

where TsO⁻ represents toluene sulfonate.